Causal relations between ischemic stroke and epilepsy: A bidirectional Mendelian randomization study

Abstract

Background: Although previous studies have reported a bidirectional relationship between ischemic stroke (IS) and epilepsy, the existence of a causal nexus and its directionality remains a topic of controversy.

Methods: The single nucleotide polymorphisms (SNPs) associated with IS were extracted from the Genome-Wide Association Study (GWAS) database. Pooled genetic data encompassing all epilepsy cases, as well as generalized and focal epilepsy subtypes, were acquired from the International League Against Epilepsy's GWAS study. In this study, the primary analysis approach utilized the inverse variance weighting (IVW) method as the main analytical technique. To enhance the robustness of the findings against potential pleiotropy, additional sensitivity analyses were conducted.

Results: In the forward analysis, the IVW method demonstrated that IS was associated with an increased risk of all epilepsy (odds ratio (OR) = 1.127, 95 % confidence interval (CI) = 1.038-1.224, P = 0.004) and generalized epilepsy (IVW: OR = 1.340, 95 % CI = 1.162-1.546, P = 5.70 × 10-5). There was no substantial causal relationship observed between IS and focal epilepsy (P > 0.05). Furthermore, generalized epilepsy, focal epilepsy, and all epilepsy did not show a causal relationship with IS.

Conclusion: This Mendelian randomization (MR) analysis demonstrates that IS increases the risk of developing epilepsy, especially generalized epilepsy. Conversely, no clear causal association was found between epilepsy and the onset of stroke. Therefore, the possible mechanisms of the effect of epilepsy on the pathogenesis of IS still need to be further investigated.

Keywords: Casual analysis; Focal epilepsy; Generalized epilepsy; Ischemic stroke; Mendelian randomization.

Fig. 1

An overall design of our bidirectional two-sample mendelian randomization analysis. GWAS, genome-wide association study; IS, ischemic stroke; MR, Mendelian randomization; SNP, single nucleotide polymorphism.

Fig. 2

Correlation analysis results of ischemic stroke and epilepsy.

Fig. 3

Sensitivity analysis of the causal effect of ischemic stroke on epilepsy. (A) Leave-one-out plot of the causal relationship between ischemic stroke and all epilepsy. (B) Leave-one-out plot of the causal relationship between ischemic stroke and generalized epilepsy. (C) Leave-one-out plot of the causal relationship between ischemic stroke and focal epilepsy.